Accelerated hyperfractionated radiochemotherapy with temozolomide is equivalent to normofractionated radiochemotherapy in a retrospective analysis of patients with glioblastoma

Abstract

BackgroundCurrent standard of treatment for newly diagnosed patients with glioblastoma (GBM) is surgical resection with adjuvant normofractionated radiotherapy (NFRT) combined with temozolomide (TMZ) chemotherapy. Hyperfractionated accelerated radiotherapy (HFRT) which was known as an option from randomized controlled trials before the temozolomide era has not been compared to the standard therapy in a randomized setting combined with TMZ.MethodsData of 152 patients with newly diagnosed GBM treated from 10/2004 until 7/2018 at a single tertiary care institution were extracted from a clinical database and retrospectively analyzed. Thirty-eight patients treated with NFRT of 60 Gy in 30 fractions (34 with simultaneous and 2 with sequential TMZ) were compared to 114 patients treated with HFRT of 54.0 Gy in 30 fraction of 1.8 Gy twice daily (109 with simultaneous and 3 with sequential TMZ). The association between treatment protocol and other variables with overall survival (OS) was assessed using univariable and multivariable Cox regression analysis; the latter was performed using variables selected by the LASSO method.ResultsMedian overall survival (OS) was 20.3 month for the entire cohort. For patients treated with NFRT median OS was 24.4 months compared to 18.5 months in patients treated with HFRT (p = 0.131). In univariable regression analysis the use of dexamethasone during radiotherapy had a significant negative impact on OS in both patient groups, HR 2.21 (95% CI 1.47–3.31, p = 0.0001). In multivariable analysis adjusted for O6-methylguanine-DNA methyl-transferase (MGMT) promotor methylation status, salvage treatment and secondary GBM, the use of dexamethasone was still a negative prognostic factor, HR 1.95 (95% CI 1.21–3.13, p = 0.006). Positive MGMT-methylation status and salvage treatment were highly significant positive prognostic factors. There was no strong association between treatment protocol and OS (p = 0.504).ConclusionsOur retrospective analysis supports the hypothesis of equivalence between HFRT and the standard protocol of treatment for GBM. For those patients who are willing to obtain the benefit of shortening the course of radiochemotherapy, HFRT may be an alternative with comparable efficacy although it was not yet tested in a large prospective randomized study against the current standard. The positive influence of salvage therapy and negative impact of concomitant use of corticosteroids should be addressed in future prospective trials. To confirm our results, we plan to perform a pooled analysis with other tertiary clinics in order to achieve better statistical reliability.

Accelerated Hyper-Versus Normofractionated Radiochemotherapy with Temozolomide in Patients with Glioblastoma: A Multicenter Retrospective Analysis.

“…The analysis indicates that HFRT yielded comparable outcomes to NFRT. This confirms previous findings that accelerated HFRT achieves treatment effects comparable to NFRT in a shorter time frame [38,39]. The lower α/β ratio of normal brain tissue for late reactions, for which an α/β value of 2Gy is widely accepted, favors a hyperfractionated acceleration instead of a hypofractionated one.…”

“…However, since prophylactic steroid administration was also performed, it cannot be considered an accurate surrogate parameter of toxicity. Previous data from Kaul et al [38] and Lewitzki et al [39] reported good tolerance of simultaneous temozolomide and HFRT.…”

“…The current treatment standard for primary GB is the combination of radiotherapy and TMZ according to the Stupp protocol [37] plus an eventual adjuvant therapy with tumor treating fields which may add a few months to the PFS and OS [4]. To the best of our knowledge, there are no prospective randomized trials investigating the efficacy of HFRT versus NFRT in combination with TMZ, with only a couple of monocentric retrospective studies reporting comparable outcomes [38,39]. To further explore any differences that might exist between HFRT and NFRT, we performed a retrospective multicenter analysis of GB patients which allowed us to model the effects of both schemes on PFS and OS while accounting for known prognostic factors.…”

The Prognostic Effect of Dexamethasone on Patients With Glioblastoma: A Systematic Review and Meta-Analysis

“…The work of Vivien Tang et al was excluded due to the small sample size (<20) to eliminate potential selection bias ( Tang et al, 2008 ). Finally, 10 articles ( Derr et al, 2009 ; Shields et al, 2015 ; Wong et al, 2015 ; Bhavsar et al, 2016 ; Dubinski et al, 2018 ; Hui et al, 2019 ; Lewitzki et al, 2019 ; Lee et al, 2020 ; Iorgulescu et al, 2021 ; Nayak et al, 2021 ) were eligible for this meta-analysis ( Figure 1 ).…”

Inhibition of HSP90 as a Strategy to Radiosensitize Glioblastoma: Targeting the DNA Damage Response and Beyond

“…Adaptive processes and an overt upregulation of the DNA damage response (DDR) have been reported to be crucial driving forces in this scenario ( 12 – 16 ). Since alternative fractionation regimens of radiotherapy have not shown relevant improvements ( 17 – 19 ), and recurrence frequently occurs within the irradiated volume ( 20 ), the question arises if biological targeting of the DDR can contribute to break GBM radiation resistance. Intriguingly, the DDR relies on high molecular weight proteins and multi-protein complexes which essentially require folding assistance and stabilization by chaperones, such as heat shock protein 90 (HSP90) ( 21 – 23 ).…”